Tissue inhibitor of metalloproteinase (TIMP) inhibits the proteolytic activity of several matrix metalloproteinases centrally involved in tumor invasion and metastases. The purpose of this study was to determine the origin of TIMP-1 mRNA production in both human colorectal cancer (CRC) and metastatic liver lesions as well as define the relationships between TIMP-1 RNA expression and standard clinicopathological variables of CRC. Total cellular RNA, extracted from 56 CRC and 10 liver metastases, were examined by Northern blot hybridization. The mean/normal mucosa fold increase of TIMP-1 RNA was significantly elevated in both CRC (12.1 +/- 1.7) and liver metastases (10.0 +/- 3.6). No relationship was noted between TIMP-1 expression and tumor size, location nor differentiation. Based on lymph node metastases status, significantly higher TIMP-1 RNA levels were found in CRC with metastases than in those without metastases (15.6 +/- 3.3 versus 7.9 +/- 1.3) (P = 0.04). Similarly, TIMP-1 RNA levels were higher in primary CRC with distant metastases than those without distant metastases (17.6 +/- 4.1 versus 9.3 +/- 1.9) (P = 0. 04). In situ hybridization localized TIMP-1 mRNA predominantly in tumor stroma within spindle fibroblast-like cells rather than in cancer cells themselves. The correlation between the increased TIMP-1 mRNA level and advanced CRC stage noted in this study reflects a possible growth-promoting function for TIMP-1 in human CRC.

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